Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Clin Cancer Res. 2012 Jul 15;18(14):3791-802. doi: 10.1158/1078-0432.CCR-11-2342. Epub 2012 May 23.
The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT).
We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles.
Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the α subunit in three CLLs carrying PIK3CA amplification.
Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL.
慢性淋巴细胞白血病（CLL）的病程在细胞遗传学组内有很大差异。我们假设 CLL 的高分辨率基因组分析将确定与首次治疗时间（TTFT）相关的其他复发性异常。
我们使用 Affymetrix 6.0 SNP 阵列对 161 例前瞻性入组的 CLL 进行了高分辨率基因组分析，并对该数据集进行了与基因表达谱的综合分析。
非进展性 CLL 的拷贝数分析（CNA）显示出稳定的基因型，每个样本中位数仅有 1 个体细胞 CNA。伴有 13q 缺失的进行性 CLL 与额外的体细胞 CNA 相关，并且 CNA 的数量越多，TTFT 的预测性就越强。我们还确定了其他与 TTFT 相关的复发性 CNA：8q24 扩增集中在 MYC 附近的癌症易感性位点，占 3.7%；3q26 扩增集中在 PIK3CA 上，占 5.6%；5%的患者存在 8p 缺失。MYC 的测序进一步确定了两个 CLL 中的体细胞突变。我们确定了哪些磷酸肌醇 3-激酶（PI3K）的催化亚基与 p85 调节亚基形成活性复合物，并在携带 PIK3CA 扩增的三个 CLL 中发现了 α 亚基的富集。
我们的研究结果表明，3q26 上集中的 PIK3CA 扩增和 8q24 上集中的 MYC 扩增与 CLL 有关。
